(370f) Effects of Spacer Arm Length and Benzoation On Enantioseparation Performance of â-Cyclodextrin Functionalized Cellulose Membranes

As most of the active pharmaceutical ingredients (API) are chiral in nature and the enantiomers often show quite different pharmacological effects, detailed analysis of pure APIs is requested by the US food and drug administration (FDA); as a result, chiral separation has become an increasingly important downstream process in the pharmaceutical industry. Membrane separation is able to provide a more promising solution to pure enantiomer production than current technologies such as asymmetric synthesis, high performance liquid chromatography (HPLC), capillary electrophoresis (CE) and preferential crystallization, because it is more cost effective, amenable to continuous operation and more easily scaled up.

We report here the effects of chiral layer position on enantioselectivity, by comparing the tryptophan enantioselectivity of membranes functionalized with chiral selectors of different spacer arm lengths, and of chiral layer thickness by using membranes grafted with mixtures of spacer arms of different lengths. The spacer arm length is the distance from the membrane surface to the chiral selector, i.e. the length of the diamine linking the β-cyclodextrins (CD) to the cellulose membranes in this case. CDs are chosen as the selector due to their tolerance to various chemical environments, lower material cost and wider applicability. 6-O-(p-Toluenesulfonyl)-β-cyclodextrin (Ts- β-CD) is reacted with ethylenediamine (EDA), diaminopropane (PDA) and diaminobutane (BDA) to synthesize the aminated beta-cyclodextrins EDA- β-CD, PDA- β-CD & BDA- β-CD, resepctively, which are subsequently grafted onto partially oxidized cellulose membranes via reductive amination. The enantioselectivity, in racemic tryptophan resolution, increases with decreasing spacer arm lengths, i.e. α_{BDA- β-CD}PDA- β-CD EDA- β-CD, while the highest selectivity of 1.20 is obtained when a mixture of chiral selectors are grafted to the membranes. The lower selectivity of membranes grafted with longer spacer arms is attributed to their lower grafting efficiency and, consequently, the presence of more defective regions; whereas the high selectivity achieved by membranes grafted with a chiral selector mixture is because of the thicker chiral layer formed, having the potential to effect more stages of interactions with the enantiomers.

Although native CDs often exhibit low enantioselectivity, higher selectivity can be realized by further derivatizing the CDs with various chemical moieties. In this study, the hydroxyl groups on the CDs are substituted with benzoate groups which can provide an increased steric hindrance to the binding of guests within the CD cavity and a restricted rotational freedom of these guests, in such a way that the chiral recognition properties of the CD is further enhanced and the notably improved enantioselectivities of 1.3-1.5 is resulted. The effect of benzoation is also proven with molecular modeling in material studio: the complex formation energies between the enantiomers and CDs with different degrees of benzoation are calculated and compared, a larger difference in complex formation energy with highly benzoated CDs is observed between enantiomer pair.